G 619, a Dual Thromboxane Synthase Inhibitor and Thromboxane A2 Receptor Antagonist, Reduces Myocardial Damage and Polymorpho-nuclear Leukocyte Accumulation following Coronary Artery Occlusion and Reperfusion in Rats

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Abstract
We investigated the effect of G 619, a dual thromboxane synthase inhibitor and thromboxane A2 (TXA2) receptor antagonist, in pentobarbital-anaesthetized rats subjected to left main coronary artery ligation (1 h) followed by reperfusion (1 h; MI/R). Sham-operated rats were used as controls (sham MI/R). Survival rate, myocardial necrosis, myocardial myelo-peroxidase (MPO) activity (investigated as an index of leukocyte adhesion and accumulation) and serum creatine phosphokinase (CPK) activity were studied. MI/R injury significantly reduced survival rate (45%), caused a marked myocardial necrosis, increased serum CPK activity (sham MI/R = 35 ± 12 U/ml; MI/R = 205 ± 13 U/ml) and produced an increase in myocardial MPO activity in the area at risk and in the necrotic area (6.3 ± 0.5 and 6.6 ± 0.9 U × 10–3/g tissue, respectively). The administration of G 619 significantly increased survival rate, lowered the area of necrosis, blunted the increase in serum CPK activity and reduced the increase in MPO activity in both the area at risk and the necrotic area. These data are consistent with an involvement of TxA2 in MI/R injury and suggest that G 619 may represent a novel therapeutic approach to the treatment of acute myocardial infarction.

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